Heparanase, is an endo-p-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size (5-7 kDa).
Expression of heparanase is restricted primarily to the placenta, platelets, keratinocytes, and activated cells of the immune system, with little or no expression in connective tissue cells and most normal epithelia. One of the prime physiological sources for heparanase is platelets.
Heparanase was recognized over the years as a pro-inflammatory and a pro-metastatic protein. It was also shown that heparanase may affect the hemostatic system in a non-enzymatic manner as it up-regulates the expression of the blood coagulation initiator—tissue factor (TF) and interact with tissue factor pathway inhibitor (TFPI) on cell surface. This activity is leading to dissociation of TFPI from the cell membrane of endothelial and tumor cells, resulting in increased cell surface coagulation activity.
Moreover, heparanase was shown to enhance TF activity resulting in increased factor Xa production and activation of the coagulation system. Heparanase was further shown to promote tumor angiogenesis in vivo.
WO2012/098542, of some of the inventors of the present invention, discloses peptides with proposed inhibitory activity to the TF/heparanase complex.
There remains an unmet need in the art for potent methods for preventing or attenuating coagulation, while not interfering with normal hemostasis, and for inhibiting the development of solid tumors.